Norepinephrine kinetics in freely moving rats

Abstract

Norepinephrine (NE) kinetics were investigated in freely moving (FM) and minimally stressed (MS) rats with the isotope dilution technique. 1) The mean NE spillover rate (NE-SOR) was 79 +/- 6 ng. kg(-1). min(-1), and the mean NE metabolic clearance rate (NE-MCR) 179 +/- 9 ml. kg(-1). min(-1) (n = 31). Thus the NE kinetics in FM and MS rats are much faster than in human beings, probably related to a higher sympathetic drive. 2) Whether the magnitude of NE-MCR is related to the level of plasma NE concentration was investigated. No significant correlation was calculated between plasma NE concentration and NE-MCR in 31 control rats. When plasma NE concentration was varied during either acute or chronic infusion of exogenous NE, NE-MCR remained unchanged as long as animal hemodynamics were not altered. When plasma NE concentration was high enough to increase mean arterial pressure (MAP), NE-MCR was decreased. However, when MAP was increased within comparable magnitude, NE-MCR was decreased during NE and increased during epinephrine (Epi) infusion. Thus the existence of an alpha-/beta-adrenergic mechanism involved in the regulation of NE-MCR independent of known hemodynamic mechanisms is suggested. 3) The "epinephrine hypothesis" was revisited in FM and MS rats. At variance with humans, very high plasma Epi concentrations have to be induced to increase NE-SOR in resting rats. Furthermore, NE-MCR was also increased, accounting for the nonsignificant increase of plasma NE concentration. Within the range of Epi concentrations with no effect on NE-SOR, an increase of NE release was revealed when the presynaptic alpha(2)-adrenoreceptors were partially inhibited by yohimbine. This suggests the existence of a second epinephrine hypothesis.

Adrenaline hypothesis: effect of formoterol on noradrenaline release

“…Kinetics data shown in Table 2 indicate a mean NA‐SOR in controls (18 ± 3 ng kg −1 min −1 ) at much lower than the mean value obtained previously (79 ± 6 ng kg −1 min −1 ) (Maignan et al ., 2001). Fig.…”

“…Alumina‐extractable [ 3 H] represents a mixture of various [ 3 H]‐labelled compounds, in which [ 3 H]‐NE accounts for a fraction only, a fraction that varies according to the time of [ 3 H]‐NA infusion and the sites of blood sampling. Our procedure was validated by paired comparison with data obtained by high performance liquid chromatography (HPLC); accordingly, control NA‐SOR and NA metabolic clearance rate (NA‐MCR) were shown to be 39.7 and 32.5% below, respectively, data obtained through HPLC procedure (Maignan et al ., 2001).…”

“…Intravenous infusion of adrenaline at 500 ng kg −1 min −1 was shown to induce no haemodynamic modification in freely moving rats and to drive the plasma concentration of adrenaline in its upper range of physiological variation with no effect on NA‐SOR; nonetheless NA‐SOR was increased when 500 ng kg −1 min −1 of adrenaline was associated with yohimbine (Maignan et al ., 2001). Thus, the effects of adrenaline (500 ng kg −1 min −1 ) were compared with those induced by an equimolar dose of formoterol (2.3 μg kg −1 min −1 ).…”

“…In freely moving rats, the NA spill over rate (NA‐SOR), as an index of the release of NA by nerve endings, is usually much higher than in humans suggesting higher sympathetic activity; further it takes an extremely high plasma adrenaline concentration to stimulate the AH pathway, suggesting a low sensitivity in the rodent compared with human beings. However, rat sensitivity to adrenaline can be improved with yohimbine, which is known to block presynaptic α 2 ‐adrenoceptors (Maignan, Legrand, Aboulfath, Safar & Cuche, 2001). Thus a yohimbine‐dependent antagonism of presynaptic α 2 ‐adrenoceptors appears to facilitate the adrenaline‐dependent stimulation of presynaptic β 2 ‐receptors to produce an increase of NA release.…”

“…A three‐step study was designed. The NA kinetics were measured in response: (a) to equimolar doses of adrenaline or formoterol to compare them; (b) to a formoterol dose with no haemodynamic effects to get rid of any activation of the baroreflex; (c) in the presence of yohimbine to measure whether blockage of presynaptic α 2 ‐adrenoceptors amplifies the NA‐SOR response to formoterol, as it did with adrenaline (Maignan et al. , 2001).…”